A dual role for autophagy in a murine model of lung cancer

• Published in: Nature communications 2014-01, Vol.5 (1), p.3056-3056, Article 3056
• Main Authors: Rao, Shuan, Tortola, Luigi, Perlot, Thomas, Wirnsberger, Gerald, Novatchkova, Maria, Nitsch, Roberto, Sykacek, Peter, Frank, Lukas, Schramek, Daniel, Komnenovic, Vukoslav, Sigl, Verena, Aumayr, Karin, Schmauss, Gerald, Fellner, Nicole, Handschuh, Stephan, Glösmann, Martin, Pasierbek, Pawel, Schlederer, Michaela, Resch, Guenter P., Ma, Yuting, Yang, Heng, Popper, Helmuth, Kenner, Lukas, Kroemer, Guido, Penninger, Josef M.
• Format: Article
• Language: English
• Subjects: 13; 13/2; 38; 38/61; 38/70; 631/67/1612; 631/80/39; 692/420/755; Animals; Autophagy - physiology; Autophagy-Related Protein 5; Disease Models, Animal; Disease Progression; Female; Gene Deletion; Gene Expression Profiling; Humanities and Social Sciences; Lung cancer; Lung Neoplasms - pathology; Lung Neoplasms - physiopathology; Male; Mice; Mice, Inbred BALB C; Microtubule-Associated Proteins - genetics; Microtubule-Associated Proteins - physiology; multidisciplinary; Mutation - genetics; Science; Science (multidisciplinary); T-Lymphocytes, Regulatory - pathology; T-Lymphocytes, Regulatory - physiology; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - physiology
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms4056

Autophagy is a mechanism by which starving cells can control their energy requirements and metabolic states, thus facilitating the survival of cells in stressful environments, in particular in the pathogenesis of cancer. Here we report that tissue-specific inactivation of Atg5 , essential for the formation of autophagosomes, markedly impairs the progression of KRas G12D -driven lung cancer, resulting in a significant survival advantage of tumour-bearing mice. Autophagy-defective lung cancers exhibit impaired mitochondrial energy homoeostasis, oxidative stress and a constitutively active DNA damage response. Genetic deletion of the tumour suppressor p53 reinstates cancer progression of autophagy-deficient tumours. Although there is improved survival, the onset of Atg5- mutant KRas G12D -driven lung tumours is markedly accelerated. Mechanistically, increased oncogenesis maps to regulatory T cells. These results demonstrate that, in KRas G12D -driven lung cancer, Atg5-regulated autophagy accelerates tumour progression; however, autophagy also represses early oncogenesis, suggesting a link between deregulated autophagy and regulatory T cell controlled anticancer immunity. Autophagy prolongs the survival of cells in stressful conditions but its role in cancer is unclear. Here, Rao et al . show that loss of the autophagic protein Atg5 enhanced cancer incidence but impaired tumour progression in a mouse model of lung cancer.